The toxicokinetics cell demography model to explain metal kinetics in terrestrial invertebrates

Ecotoxicology, Nov 2012

Metal toxicokinetics in invertebrates are usually described by one-compartment first-order kinetic model. Although the model gives an adequate description of the toxicokinetics in certain cases, it has been shown to fail in some situations. It also does not seem acceptable on purely theoretical grounds as accumulation and excretion rates may change depending on instantaneous toxicant concentration in the gut. We postulate that the mechanism behind such changes is connected with the toxic effect of metals on gut epithelial cells. Based on published data, we have constructed a mechanistic model assuming a dynamic rate of replacement of epithelial cells with increasing contamination. We use a population-type modeling, with a population of gut epithelial cells characterized by specific death and birth rates, which may change depending on the metal concentration in food. The model shows that the equilibrium concentration of a toxicant in an organism is the net result of gut cell death and replacement rates. At low constant toxicant concentrations in food, the model predicts that toxicant-driven cell mortality is moderate and the total amount of toxicant in the intestine increases slowly up to the level resulting from the gradual increase of the cell replacement rate. At high constant concentration, total toxicant amount in the gut increases very fast, what is accompanied by massive cell death. The increased cell death rate results in reduced toxicant absorption, which in turn brings its body load down. The resulting pattern of toxicokinetic trajectory for high metal concentration closely resemble that found in empirical studies, indicating that the model probably describes the actual phenomenon.

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The toxicokinetics cell demography model to explain metal kinetics in terrestrial invertebrates

Krzysztof Argasinski 0 Agnieszka Bednarska 0 Ryszard Laskowski 0 0 K. Argasinski (&) A. Bednarska R. Laskowski Institute of Environmental Sciences, Jagiellonian University , Gronostajowa 7, 30-387 Krakow, Poland Metal toxicokinetics in invertebrates are usually described by one-compartment first-order kinetic model. Although the model gives an adequate description of the toxicokinetics in certain cases, it has been shown to fail in some situations. It also does not seem acceptable on purely theoretical grounds as accumulation and excretion rates may change depending on instantaneous toxicant concentration in the gut. We postulate that the mechanism behind such changes is connected with the toxic effect of metals on gut epithelial cells. Based on published data, we have constructed a mechanistic model assuming a dynamic rate of replacement of epithelial cells with increasing contamination. We use a population-type modeling, with a population of gut epithelial cells characterized by specific death and birth rates, which may change depending on the metal concentration in food. The model shows that the equilibrium concentration of a toxicant in an organism is the net result of gut cell death and replacement rates. At low constant toxicant concentrations in food, the model predicts that toxicant-driven cell mortality is moderate and the total amount of toxicant in the intestine increases slowly up to the level resulting from the gradual increase of the cell replacement rate. At high constant concentration, total toxicant amount in the gut increases very fast, what is accompanied by massive cell death. The increased cell death rate results in reduced toxicant absorption, which in turn brings its body load down. The resulting pattern of toxicokinetic trajectory for high metal concentration closely resemble that found in empirical studies, indicating that the model probably describes the actual phenomenon. - Classic toxicokinetic modelcritique Toxicokinetics (TK) was an important area of research well before ecotoxicology has been invented. Understanding the kinetics of a toxic chemical is the very basis for studies on its distribution and toxicity in an organism. Not surprisingly, specific TK models have been developed in pharmacology and medicine to describe and predict the behavior and fate of toxic chemicals (and drugs alike) in animals. Physiology-based pharmacokinetic (PBPK) models can be fairly complicated; they incorporate a number of different body parts (compartments: the intestine, liver, kidneys, etc.) and processes (absorption, distribution, metabolism, excretion). In ecotoxicology, and especially in the case of metal TK, metabolism is usually neglected (metals cannot be degraded like pesticides), and only absorption and excretion rates are studied. This simplifies the model greatly, still allowing the internal concentrations of metals to be predicted in animals inhabiting metal-polluted environments. The TK of metals traditionally have been described by a simple one-compartment two-phase model which assumes that the net metal accumulation rateand hence its final body concentrationdepends on the balance between the metal absorption rate ka and excretion rate ke. The process can be described as a system of linear differential equations. In the classic one-compartment toxicokinetic model (Atkins 1969) the dynamic of internal concentration of a toxic chemical, C_int, which is absorbed at rate ka from the external environment (e.g., food), contaminated at concentration Cext, and eliminated from the organism at rate ke, is described by the equation: Although in some cases such a model describes metal kinetics satisfactorily, it is actually not a proper description of the underlying mechanisms but only a good approximation as the approach is purely phenomenological. The classic one-compartment model allows only for an asymptotic approach to a stable concentration resulting directly from the balance between ka and ke, which are constant throughout the exposure period. Although broadly accepted and used in TK modeling, such an approach seems neither confirmed by data (Janssen et al. 1991; Lagisz et al. 2005) nor reasonable from the biological point of view. Moreover, the model relies on the assumption of linearity of absorption and excretion processes but our recent studies indicated that under certain circumstances the two-phase model does not fit the trajectory of metal concentrations in animals exposed to metalcontaminated food (Bednarska et al. 2011; Laskowski et al. 2010). A number of other studies also showed similar deviations from the classical two-phase model (Descamps et al. 1996; Lagisz et al. 2005; Janssen et al. 1991). A change in the physiology of metal regulation as an outcome of poisoning of gut epithelial cells and replacement of dead cells with new ones is one of the mechanisms we suggested to explain nickel TK in our previous work on nickel TK in the ground beetle Pterostichus oblongo (...truncated)


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Krzysztof Argasinski, Agnieszka Bednarska, Ryszard Laskowski. The toxicokinetics cell demography model to explain metal kinetics in terrestrial invertebrates, Ecotoxicology, 2012, pp. 2186-2194, Volume 21, Issue 8, DOI: 10.1007/s10646-012-0972-6